9,10-diazatricyclo[4,4,1,12,5 ] decane and 2,7-diazatricyclo [4,4,0,03,8 ] decane derivatives having analgesic activity

ABSTRACT

9,10-DIAZATRICYCLO[4,4,1,1 2 ,5 ]DECANE (la) AND 2,7-DIAZATRICYCLO[4,4,0,0 3 ,8 ]DECANE (1b) DERIVATIVES HAVING ANALGESIC ACTIVITY. ##STR1##

This application is a 371 of PCT/EP 98/02252 filed Apr. 4, 1998.

The present invention relates to 9,10-diazatricyclo[4.2.1.1²,5 ]decaneand 2,7-diazatricyclo[4,4,0,0³,8 ]decane derivatives having analgesicactivity.

WO 95/23152 and WO 94/16698 disclose 3,8-diazabicyclo[3.2.1]octanederivatives having central analgesic activity, wherein the two nitrogenatoms are respectively substituted with acyl groups and aryl orheteroaryl-acrylic groups. Said compounds proved to be particularlyactive as central analgesics and are characterized by satisfactorytolerability and poor or no induction of addiction and tolerance.

Now it has been found that analogues of two novel tricyclic systems,characterized by two endoethylenic bridges on the piperazine ring, havean even higher analgesic activity.

The compounds of the invention have the following general formulae:##STR2## in which R₁ and R₂ are both hydrogen or are different from eachother, and are selected from hydrogen; C₁ -C₈ alkyl; C₂ -C₁₀ acyl; an Argroup wherein Ar is optionally substituted phenyl, optionallysubstituted naphthyl, an heterocyclic group containing 1 to 3heteroatoms selected from oxygen, nitrogen and sulphur having 5 to 7ring atoms, optionally benzofused and optionally substituted at thebenzene ring; a group of formula --CH₂ --CH═CH--Ar wherein Ar is asdefined above.

Examples of Ar groups can be represented by the following formulae##STR3## wherein X, Y and Z, which are the same or different, areselected from N, NH, S, O, ═(CH)_(n) or --(CH₂)_(n) -- wherein n=0-2 andR is hydrogen or a substituent selected from halogen atoms, nitro,amino, methoxy, ethoxy, C₁ -C₆ alkylamino or C₁ -C₈ acylamino groups.

Preferably, R₁ is a C₂ -C₁₀ acyl group and R₂ is an Ar group or --CH₂--CH═CH--Ar as defined above.

A C₂ -C₁₀ acyl group is preferably acetyl, propionyl or butyryl, morepreferably propionyl.

R₂ is preferably a group of formula --CH₂ --CH═CH--Ar

wherein Ar is phenyl or substituted phenyl, more preferably phenyl.

The compounds of formulae I and Ib can be prepared according to thefollowing schemes: ##STR4##

In the schemes reported above, X is a reactive group suitable for thedesired N-alkylation or N-acylation reaction, for example a halogenatom, a mesyl, tosyl, acyl chloride, anhydride group and the like.

The process according to the invention comprises the reaction of5,6-epoxycyclooctene III, easily obtainable from commercially available1,5-cyclooctadiene II, with benzylamine in dichloromethane, in thepresence of ytterbium (III) trifluoromethanesulfonate, to giveaminoalcohol IV.

The alcohol group is then transformed into the corresponding sulphateester which is refluxed in concentrated sodium hydroxide to yieldaziridine V. The latter is treated with sodium azide and ammoniumchloride with heating in ethanol and water to yield amino-azide VI,which is transformed into the compounds VIIa and VIIb by addition ofbromine. The dibromo derivatives cannot be isolated as an intramolecularcondensation occurs.

The compounds VIIa and VIIb are separated by chromatography according toconventional techniques.

The compounds VIIa and VIIb can then be converted into compounds offormula VIIIa or VIIIb, respectively, by treatment withtriphenylphosphine in tetrahydrofuran and subsequent addition of water.

Conventional N-alkylation or N-acylation reactions, in suitablesequence, allow then to prepare the desired compounds.

The compounds of formula Ia and Ib have affinity to opioid receptors,evaluated according to the method described by Wood et al.,Neuropharmacology, 1981, 20, 1219, which is up to 5-fold higher thanthat of the compounds described in WO 95/23152 and WO 94/16698.

The compounds of the invention, optionally in the form ofpharmaceutically acceptable salts, can conventionally be formulated inpharmaceutical compositions suitable for the oral, parenteral or rectaladministration. The daily dosage will, of course, depend on a number offactors, but it will generally range from 1 mg to 100 mg/day, optionallysubdivided in more administrations.

The following example shows the invention in greater detail.

EXAMPLE

Trans-2-benzylamino-5-cycloocten-1-ol (IV)

To a stirred solution of 5,6-epoxycyclooctene III (10.0 g, 0.081 mol) indry CH₂ Cl₂ (100 ml) kept under nitrogen atmosphere, benzylamine (10.35g, 0.097 mol) and Ytterbium(III) trifluoromethanesulfonate (4.96 g,0.008 mol) were added and the mixture was stirred for 24 hrs at roomtemperature. Extractive work-up of the reaction mixture with water andCH₂ Cl₂ gave the title product as a white solid (yield 83%). m.p.:70-71° C., b.p:140° C./1 mm Hg. ¹ H NMR (CDCl₃): δ 7.59-7.56 (m, 2H,ArH), 7.38-7.35 (m, 3H, ArH), 5.64-5.44 (m, 2H, CH═CH), 5.42-5.00 (bs,D₂ O exchangeable, OH) 4.07 (AB syst, 2H, J=12.57 Hz, PhCH₂), 3.75-3.65(m, 1H, CHOH), 3.00-3.15 (m, 1H, CHNH--), 2.35-2.02 (m, 6H), 1.95-1.42(m, 2H).

Trans-2-benzylamino-5-cycloocten-1-ol sulphate ester

To a suspension of compound IV (2.6 g, 0.011 mol) in anhydrous ether (50ml) kept under vigorous stirring at 0-5° C., chlorosulfonic acid (1.6 g,0.011 mol) was added dropwise. The reaction mixture became gummy anddifficult to stir. However, after stirring overnight at roomtemperature, the white solid that separated was filtered and washed withether, yielding 3.2 g (93%) of the sulphate ester, m.p 162-163° C.

¹ H NMR (CDCl₃): δ 8.50-8.00 (bs D₂ O exchangeable, 1H, ⁺ NH); 7.50-7.30(m, 5H, ArH); 5.70-5.50 (m, 1H, CH═CH); 5.50-5.30 (m, 1H, CH═CH);4.70-4.50 (m, 1H, CHOSO₃ ⁻); 4.40-4.00 (m, 2H, PhCH₂); 3.50-3.30 (1H,CHN); 2.60-1.70 (m, 8H).

N-Benzyl-9-azabicyclo[6.1.0]-4-nonene (V)

The sulphate ester (4 g, 0.017 mol) was dissolved in a 33% sodiumhydroxide solution (40 ml) and the mixture was refluxed for 2 hrs,cooled, saturated with potassium hydroxide and extracted with 3×50 mlethyl acetate. The organic layers were collected, dried (Na₂ SO₄) andthe solvent evaporated to give the desired compound isolated by silicagel flash chromatography, eluting with CH₂ Cl₂ /Ethyl acetate 9:1 (yield62%). B.p.:125° C./1 mm Hg.

¹ H NMR (CDCl₃): δ 7.39-7.15 (m, 5H, ArH), 5.64-5.45 (m, 2H CH═CH), 3.55(s, 2H, PhCH₂), 2.50-2.25 (m, 2H, CHN) 2.20-1.90 (bm, 6H) 1.61-1.45 (m,2H).

Trans-2-azido-1-benzylamino-5-cyclooctene

A solution of compound V (10 g, 0.047 mol), sodium azide (12.2 g, 0.19mol), and ammonium chloride (10.02 g, 0.19 mol) in ethanol (500 ml) andwater (100 ml) was refluxed for 4 hrs. Ethanol was evaporated off andthe aqueous mixture was extracted with 3×150 ml CH₂ Cl₂. The organiclayers were collected, dried (Na₂ SO₄) and the solvent evaporated togive the desired compound which was isolated as an oil by silica gelflash chromatography, eluting with CH₂ Cl₂ /Ethyl acetate 9:1 (yield91%).

¹ H NMR (CDCl₃): δ 7.35-7.10 (5H, ArH), 5.60 (dq, 2H, J=5.5, CH═CH),3.80 (AB syst, 2H, J=12.82, PhCH₂), 3.67 (dt, 1H, J=8.8, CHN₃);3.00-2.75 (m, 1H, CHN); 2.60-2.30 (m, 2H); 2.25-2.00 (m, 4H); 1.90-1.60(m, 2H).

2-β-Bromo-5-azido-9-benzyl-9-azabicyclo[4.2.1.]nonane (VIIa)

2-β-Bromo-6-azido-9-benzyl-9-azabicyclo[3.3.1.]nonane (VIIb)

To a solution of trans-2-azido-1-benzylamino-5-cyclooctene (2 g, 7.8mmol) in cyclohexane (110 ml), stirred at 5° C. in subdued light, wasslowly added a solution of 10% bromine in cyclohexane, until a yellowcolour persisted in the reaction mixture. The solid which separated wasfiltered (1.6 g), treated with 10% sodium hydroxide and the bases thusliberated were extracted with ether. The organic layer was dried on Na₂SO₄ and the solvent evaporated. Flash chromatography on silica geleluting with petroleum ether 40-60/diethyl ether 98:2 gave firstcompound VIIa as an oil (yield 23%), further elution gave compound VIIbas a white solid m.p. 75-76° C. (diethyl ether) (yield 19%).

VIIa: ¹ H NMR (CDCl₃): δ 7.45-7.20 (m, 5H, ArH); 4.12 (t, 1H, J=7.2,CHBr); 3.90-3.70 (m, 3H, PhCH₂, CHN); 3.56 (q, 1H, J=4.8, CHN₃);3.40-3.20 (m, 1H, CHN); 2.40-2.10 (m, 3H); 2.10-1.70 (m, 3H); 1.60-1.20(m, 2H).

VIIb: ¹ H NMR (CDCl₃): δ 7.45-7.20 (m, 5H, ArH); 4.50-4.30 (m, 1H,CHBr); 4.20-3.90 (m, 3H, PhCH₂, CHN₃); 3.20-3.00 (m, 1H, CHN); 3.00-2.90(mn, 1H, CHN); 2.50-2.00 (m, 5H); 2.00-1.60 (m, 3H).

2-β-Bromo-5-iminophosphorane-9-benzyl-9-azabicyclo[4.2.1.]nonane

To a stirred solution of VIIa (0.4 g, 0.0012 mol) in dry tetrahydrofuranat room temperature, a stoichiometric amount of triphenylphosphine,dissolved in THF, was added dropwise, and the mixture was refluxed for 4hrs, then cooled and added with HCl in diethyl ether. The resultingsolid was filtered, treated with 20% NaHCO₃ and extracted with ethylacetate. The organic layers were dried over Na₂ SO₄ and the solvent wasevaporated off. Flash chromatography eluting with diethyl ether/6 M NH₃in methanol 95:5 gave the title compound in quantitative yields, m.p.114-115° C.

9-Benzyl-9,10-diazatricyclo[4.2.1.1²,5 ]decane (VIIIa)

A solution of the above compound (0.35 g, 0.6 mmol) in THF (9 ml) andwater (0.1 ml) was refluxed for 15 hrs. After cooling, HCl was bubbledthrough the mixture, the resulting solid was decanted and separated fromthe liquid, the solvents and the excess HCl were removed byco-evaporation with ethanol. The title compound as hydrochloride waswashed with diethyl ether and crystallised (MeOH/Et₂ O) to give an 85%yield. m.p. (as free base) 75-76° C.

¹ H NMR (CDCl₃): δ 7.50-7.10 (m, 5H, ArH); 3.50 (s, 2H, PhCH₂),3.20-3.00 (m, 2H, CHN); 2.90-2.70 (m, 2H, CHN); 2.20-2.00 (m, 2H);1.90-1.70 (m, 4H); 1.60-1.40 (m, 2H).9-Benzyl-2,7-diazatricyclo[4,4,0,0,³,8 ]decane (VIIIb)

To a stirred solution of VIIb (10.3 g, 0.0031 mol) in anhydrous THF (30ml) at room temperature, a stoichiometric amount of triphenylphosphinedissolved in THF was added and the mixture refluxed for 7 hrs. Aftercooling, water (0.1 ml) was added and the mixture refluxed overnight.The reaction was quenched as described for compound VIIIa. Flashchromatography eluting with diethyl/ether/6M NH₃ in MeOH 95:7 gave thetitle compound (yield 56%). m.p. (as free base) 127-128° C.

¹ H NMR (CDCl₃): δ 7.50-7.10 (m, 5H, ArH); 3.90 (AB syst, 2H, J=13.7,PhCH₂), 3.20-3.00 (m, 2H, CHN); 2.80-2.60 (m, 2H, CHN); 2.30-1.50 (m,8H).

9,10-Diazatricyclo[4.2.1.1²,5 ]decane Ia'

2,7-Diazatricyclo[4,4,0,0,³,8 ]decane Ib'

Compounds VIIIa and VIIIb hydrochlorides (0.14 g, 0.57 mmol) weredissolved in ethanol (6 ml). To this solution 10% w/w palladium oncarbon was added together with a few μl of 6N hydrochloric acid. Themixture was hydrogenated at room temperature overnight, the catalyst wasfiltered off and washed with hot 50% ethanol in water. The filtrate wasevaporated in vacuo to give the title compounds as hydrochlorides aswhite solids in quantitative yields.

Ia': m.p. 295° C. (EtOH/H₂ O/Et₂ O)

Ib': m.p. 300° C. (EtOH/H₂ O/Et₂ O).

¹ H NMR (DMSO): δ 8.80 (bs, D₂ O exchang., 2H, ⁺ NH.HCl); 3.94 (app.s,4H, CHN); 2.40-2.20 (m, 4H); 2.20-2.00 (m, 4H).

3.2HCl: m.p. 300° C. dec (EtOH/H₂ O/Et₂ O).

¹ H NMR (D₂ O): δ 4.04 (app.d, 4H, CHN); 2.50-2.20 (m, 4H); 2.20-1.90(m, 4H).

9-Propionyl-9,10-diazatricyclo[4.2.1.1.²,5 ]decane 1a"

9-Propionyl-2,7-diazatricyclo[4,4,0,0³,8 ]decane 1b"

A solution of propionic anhydride (6.9 mmol) in CH₂ Cl₂ (2 ml) was addedin one portion to an ice cooled solution of the appropriate benzylderivative VIIIa or VIIIb (0.45 g, 1.9 mmol) in CH₂ Cl₂ (15 ml). Themixture was refluxed for 1 h, allowed to cool to room temperature,alkalinized with a 40% sodium hydroxide excess and stirred overnight.Extraction with dichloromethane and drying yielded9-propionyl-10-benzyl-derivatives (100%) which were hydrogenated asdescribed above to give the title compounds as hydrochlorides (yield96%).

Ia": m.p. 230° C.

Ib": m.p. 234° C.

9-Propionyl-10-cinnamyl-9,10-diazatricyclo[4.2.1.1.²,5 ]decane Ia'"

2-Propionyl-7-cinnamyl-2,7-diazatricyclo[4,4,0,0³,8 ]decane Ib'"

A mixture of the suitable propionyl derivative Ia" or Ib" (1.1 mmol),cinnamyl chloride (1.1 mmol), K₂ CO₃ (1.1 mmol) in acetone was refluxedfor 24 hrs. The inorganic salts were filtered off, the filtrate wasevaporated and the residue purified by silica gel flash chromatography,eluting with petroleum ether 40-60/ethyl acetate. The title compoundswere obtained in 85-95% yields.

Ia'": m.p. 189-190° C.

Ib'": m.p. 220-221° C.

Operating analogously to the procedure described above, using thesuitable derivatives of m-chlorocinnamic, p-nitrocinnamic,3-α-naphthyl-propionic acids, the following compounds were obtained:

9-propionyl-10-(m-chlorocinnamyl)-9,10-diazatticyclo[4.2.1.1²,5]decane.HCl.H₂ O; m.p.=90° C.,

9-propionyl-10-(p-nitrocinnamyl)-9,10-diazatricyclo[4.2.1.1²,5 ]decanefree base m.p.=132-133° C.,

9-propionyl-10-(3'α-naphthylpropenyl)-9,10-diazatricyclo[4.2.1.1.sup.2,5]decane.HCl.2H₂ O; m.p.=138-142° C.,

2-propionyl-7-(p-nitrocinnamyl)-2,7-diazatricyclo[4,4,0,0³,8]decane.HCl.1/2H₂ O; m.p.=135° C.

What is claimed is:
 1. Compounds of formula (I): ##STR5## wherein R₁ andR₂ are both hydrogen or are different from each other, and are selectedfrom hydrogen; C₁ -C₈ alkyl; C₂ -C₁₀ acyl; an Ar group wherein Ar isoptionally substituted phenyl, optionally substituted naphthyl, anheterocyclic group containing 1 to 3 heteroatoms selected from oxygen,nitrogen and sulphur having 5 to 7 ring atoms, optionally benzofused andoptionally substituted at the benzene ring; a group of formula --CH₂--CH═CH--Ar wherein Ar is as defined above.
 2. Compounds according toclaim 1, wherein Ar groups are selected from ##STR6## wherein X, Y andZ, which are the same or different, are selected from N, NH, S, O,═(CH)_(n) or --(CH₂)_(n) -- wherein n=0-2 and R is hydrogen or asubstituent selected from halogen atoms, nitro, amino, methoxy, ethoxy,C₁ -C₆ alkylamino or C₁ -C₈ acylamino groups.
 3. Compounds according toclaim 1, wherein R₁ is a C₂ -C₁₀ acyl group and R₂ is an Ar group or--CH₂ --CH═CH--Ar as defined above.
 4. Compounds according to claim 1wherein the C₂ -C₁₀ acyl group is acetyl, propionyl or butyryl. 5.Compounds according to claim 1 wherein R₂ is a group of formula --CH₂--CH═CH--Ar wherein Ar is phenyl or substituted phenyl. 6.Pharmaceutical compositions containing a compound of claim 1 as theactive ingredient.
 7. A method for relief of pain in an animal sufferingfrom pain, comprising administering to said animal an analgesiceffective amount of a compound of claim 1.